TW201924661A - Solid dispersion comprising fimasartan - Google Patents

Abstract

The present invention relates to a solid dispersion containing fimasartan, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof; and a pharmaceutically acceptable substrate. The solid dispersion according to the present invention increases solubility of fimasartan, raises dissolution thereof, and thus improves bioavailability thereof.

Description

Non-masartan solid dispersion

The present invention relates to a solid dispersion comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable base. The solid dispersion of the present invention increases the solubility of non-masartan, improves its dissolving effect, and further increases its bioavailability.

In addition to the pharmacological activity of a drug, in the field of medicine, the physico-chemical properties of a drug also have a significant effect on the onset time of a drug's titer.

For example, if the drug is poorly water-soluble, although it has excellent pharmacological activity, its dissolution during oral intake is not good, which may make it difficult for the drug to exert its effect. This condition is difficult to dissolve the drug into a finished product because it is difficult to dissolve. Even if the drug is formulated into a finished product, its low solubility may cause great deviations in the dissolution rate of the drug from different finished products, and cause the problem of low dissolution rate.

In addition, if the bioavailability of the drug is low, despite its excellent pharmacological activity, the concentration of the drug in the blood during oral administration may become low, resulting in the inability to obtain a sufficient therapeutic effect. In order to obtain a sufficient therapeutic effect, it may be necessary to increase the dose of an oral drug, which may cause problems such as poor drug compliance or concomitant side effects.

Therefore, no matter how excellent the pharmacological activity of the drug, many methods have been tried to enhance the solubility of the drug and its bioavailability during oral administration, so that the drug can exert its full effect.

Femaracetam is a hypertension drug, which is an angiotensin II receptor antagonist. It is currently available under the trade name Kanarb in three doses of 30, 60, and 120 mg. The main ingredients of the product Is non-masartan potassium salt.

In summary, if the physical and chemical properties such as solubility are excellent, there will be various advantages such as increased bioavailability. Therefore, many efforts have been made to improve the solubility and bioavailability of non-masartan, its pharmaceutically acceptable salts, or its hydrates or solvates.

Prior art literature

Patent documents

(Patent Document 1) International Patent Publication No. WO1999-055681

technical problem

It is an object of the present invention to provide a solid dispersion containing femasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable base.

Another object of the present invention is to provide a pharmaceutical composition containing the aforementioned solid dispersion and a pharmaceutically acceptable additive.

Technical solutions

The present invention provides a solid dispersion including femasartan represented by the following general formula 1, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable base.

[Formula 1]

The solid dispersion described herein means that fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is dispersed in a pharmaceutically acceptable matrix. Regarding the distribution form, fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may be dispersed in the form of small particles or very small particles, and may be dispersed in a pharmaceutically acceptable form The matrix is in its molecular unit.

The solid dispersion of the present invention increases the solubility of non-masartan, improves its dissolving effect, and further increases its bioavailability. Femartan is a poorly water-soluble drug with low solubility, so femartan is not easy to formulate into finished products and the bioavailability is not high enough. Therefore, in order for fumasartan to have a sufficient therapeutic effect by oral administration, it is necessary to include a high content of fumasartan in the finished product. As a result, patients have poor compliance with the drug. In view of the foregoing, prior art has used non-masartan potassium salts instead of non-masartan. The solid dispersion of the present invention contains non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable matrix, and has excellent physicochemical and pharmacological properties, such as a drug The required solubility, bioavailability, etc., enable the solid dispersion to exhibit more excellent physical properties, making it easier to formulate into a finished product. Compared to traditional non-masartan potassium salts, the solid dispersions of the present invention can improve patient compliance with drugs.

In one embodiment of the present invention, the matrix is not limited to a specific matrix, as long as the matrix is pharmaceutically acceptable and can form a solid dispersion. That is, the aforementioned matrix may dissolve or disperse non-masartan, and may particularly be a polymer-type excipient or a non-polymer-type excipient.

In one embodiment of the present invention, the pharmaceutically acceptable matrix is a polymer-based excipient.

In an embodiment of the present invention, the polymer-based excipient may be selected from hydroxyalkyl methyl cellulose (for example, hydroxypropyl methyl cellulose), hydroxyalkyl cellulose (for example, hydroxypropyl fiber). Cellulose or hydroxyethyl cellulose), carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose succinate (for example, hydroxypropyl methyl cellulose acetate succinate), phthalic acid fibers (Eg, hydroxypropyl methyl cellulose phthalate), polymethacrylate (eg, eudragit (registered trademark of Eudragit) type), polyhydroxyalkyl acrylate, polyhydroxyalkyl methacrylate , Polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, cross-linked polyvinylpyrrolidone (crospovidone), polyalkylene glycol (for example, polyethylene glycol), polymer One of the groups consisting of ethylene oxide, poloxamer, polyvinyl acetate, vinyl alcohol / vinyl acetate copolymer, xanthan gum, keto acid, alginic acid and its salts, polylactic acid and dextrin Or two or more, the present invention is not limited thereto.

In another embodiment, the pharmaceutically acceptable matrix is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), and polymethacrylate. One or two or more of the group.

In one embodiment of the present invention, the polymethacrylate is Eudragit EPO.

In one embodiment of the present invention, the pharmaceutically acceptable matrix is a non-polymeric excipient.

In one embodiment of the present invention, the non-polymeric excipient may be sugar and / or sugar alcohol and / or cyclodextrin. For example, non-polymeric excipients may include sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, threitol, ribitol, arabinol Sugar alcohol, xylitol, galactitol, inositol, trehalose, isitol (isomalt), inulin, maltodextrin, β-cyclodextrin, hydroxypropyl-β -Cyclodextrin, sulfobutyl ether cyclodextrin or a mixture thereof, but the invention is not limited thereto.

In another embodiment of the present invention, the weight ratio of non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a pharmaceutically acceptable matrix is 1: 0.1 to 1:10.

In one embodiment of the present invention, the pharmaceutically acceptable salt of non-masartan may be a salt commonly used in the pharmaceutical industry.

In an embodiment of the present invention, the pharmaceutically acceptable salts of non-masartan may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonates, amino acid salts, and amine salts. Group. In particular, the pharmaceutically acceptable salts of non-masartan may be inorganic ion salts prepared from calcium, potassium, sodium, magnesium and the like. An inorganic acid salt prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, and the like. By acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid , Galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, almond acid, mucic acid, pamoic acid, pantothenic acid, amber Organic acid salts prepared from acids, stannic acids, etc. Sulfonate prepared from methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalenedisulfonic acid, naphthalenesulfonic acid, and the like. An amino acid salt prepared from glycine, arginine, lysine and the like. An amine salt prepared from trimethylamine, meglumine, triethylamine, ammonia, pyridine, methylpyridine, choline and the like. However, the type of salt in the present invention is not limited to the salts listed here.

The hydrate of non-masartan or a pharmaceutically acceptable salt thereof of the present invention may contain stoichiometric or non-stoichiometric water, which is bonded by non-covalent intermolecular forces. When the amount of non-masartan or its salts is 1 equivalent, the hydrate may contain at least 1 equivalent, that is, 1 to 5 equivalents of water.

The solvate of non-masartan or a pharmaceutically acceptable salt thereof of the present invention may contain a stoichiometric or non-stoichiometric solvent, which is bonded through intermolecular forces.

In an embodiment of the present invention, the non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may be selected from the group consisting of non-masartan free base, non-masartan potassium, and A group of sartan potassium trihydrate, non-masartan potassium monohydrate, non-masartan tosylate, and non-masartan ammonium salt. In particular, the pharmaceutically acceptable salt of non-masartan may be non-masartan potassium, non-masartan tosylate or non-masartan ammonium salt. In particular, the pharmaceutically acceptable hydrate of non-masartan or a salt thereof may be non-massartan potassium monohydrate or non-massartan potassium trihydrate.

The solid dispersion of the present invention can be prepared by a conventional method for preparing a solid dispersion.

In one embodiment of the present invention, a solid dispersion containing non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable matrix can pass through, but is not limited to, a mobile layer. A granulated machine (fluidized bed granulator) was used for the preparation.

For example, a solid dispersion can be prepared in the manner described above such that a solution containing non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable base is sprayed onto the medicine Mixtures of acceptable additives are, for example, mannitol, dicalcium phosphate, and sodium starch glycolate.

In one embodiment of the present invention, a pharmaceutical composition for preventing or treating angiotensin II receptor-related diseases is provided, which includes the solid dispersion as described above and a pharmaceutically acceptable additive.

In one embodiment of the present invention, a solid dispersion system containing femasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is used as an angiotensin II receptor inhibitor.

In an embodiment of the present invention, the solid dispersion may include a pharmaceutically acceptable additive, and may be separately provided from the solid dispersion to form a pharmaceutical composition.

"Pharmaceutically acceptable" can mean physiologically acceptable. When applied to the human body, it usually does not cause allergic reactions, such as gastrointestinal disturbance and dizziness, or other similar reactions, and is commonly used by those skilled in the art to prepare pharmaceutical compositions.

Pharmaceutically acceptable additives can be carriers, excipients, extenders, antioxidants, buffer solutions, fillers, anticoagulants, lubricants, humectants, flavoring agents, emulsifiers, suspending agents, and surfactants. , Preservatives, etc. By way of example, the additive may be lactose, dextrose, calcium silicate, corn starch, sodium hydroxymethyl starch, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia (Acacia rubber), alginate, gelatin, calcium phosphate, dicalcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, sodium methylol starch, croscarmellose sodium, Cross-linked polyvinyl pyrrolidone (crospovidone), polyvinyl pyrrolidone, hydroxypropyl methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, light anhydrous silicic acid, talc, stearic acid, stearic acid Magnesium, calcium stearate, gelatin, mineral oil, salt solution, aqueous glucose solution, similar aqueous sugar solution, ethanol, glycol, ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride Or a mixture thereof. However, the aforementioned listed additives are only examples, and do not limit the additives that can be included in the composition of the present invention. Preferred additives may be mannitol, dicalcium phosphate and sodium methylol starch.

The pharmaceutical composition of the present invention can be formulated into a product according to a conventional method, and can be made into an oral administration product or a parenteral administration product, preferably an oral administration product.

In the present invention, a product for oral administration may be a solid product such as a lozenge, a pill, a powder, a granule, a capsule, or the like, or a liquid product such as a suspension, an internal liquid, an emulsion, a syrup, or the like. Preferred are solid products, more preferred are lozenges.

In another embodiment of the invention, the pharmaceutical composition is in the form of a granule, capsule or lozenge.

In the present invention, granules, capsules or lozenges can be prepared by conventional product methods.

In an embodiment of the present invention, a lozenge can be prepared by a direct compression method, the aforementioned solid dispersion is mixed with a pharmaceutically acceptable additive, and the resulting mixture is directly pressed into the lozenge. Alternatively, the granules are prepared by dry granulation and then pressed into a tablet. Examples of the pharmaceutically acceptable additive may be the same as described above. For example, mannitol, croscarmellose sodium, and magnesium stearate can be mentioned.

The solid dispersion of the present invention has excellent physicochemical properties, such as processability of a dosage form required for preparing a pharmaceutical agent. Therefore, when the solid dispersion is formulated into a dosage form such as a lozenge or capsule, a lozenge or capsule having a uniform pharmacological effect can be prepared without causing a problem of deterioration of the pharmacological effect during the formulation process. Therefore, a product having excellent remedial effect and uniform pharmacological effect can be produced at low cost.

In the present invention, the content of the additives contained in the pharmaceutical composition is not particularly limited, and can be appropriately adjusted within the range of commonly used content for formulating finished products.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically), wherein the dosage may be based on the weight, age, sex, health status, and diet of the patient , Administration time, administration method, administration period or interval, excretion rate, composition specificity, product nature, disease severity, etc., can be adjusted within its scope.

In one embodiment of the present invention, the pharmaceutical composition is used to prevent or treat angiotensin II receptor-related diseases, wherein the aforementioned diseases are selected from the group consisting of stroke, cerebral apoplexy, cerebral hemorrhage, cerebral infarction, and One or two of the groups consisting of Zheimer's disease, vascular dementia, Kouja's disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure and inflammation Or more.

In the present invention, in addition to non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable matrix, the pharmaceutical composition may further include other substances having pharmacological activity. The pharmacologically active substance may also have the same pharmacological activity as non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or may have other pharmacological activity. The other pharmacologically active substance contained in the pharmaceutical composition may be a therapeutic agent for hyperlipidemia, such as amlodipine, lercardipine, nicardipine, simvastatin, Atorvastatin, pravastatin, rosuvastatin, etc .; diabetes treatments such as metformin, hydrochlorothiazide, sitagliptin, vitagliptin (Vildagliptin), ligagliptin (linagliptin), saxagliptin, teneligliptin, anagliptin, melogliptin, dutogliptin, Gemigliptin and the like, pharmaceutically acceptable salts thereof, or mixtures thereof. More preferred are amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, sitagliptin, vilagliptin, ligagliptin, a pharmaceutically acceptable salt thereof, or a mixture thereof.

The pharmaceutical composition of the present invention can be used alone or in combination with surgery, endocrine therapy, drug treatment, and methods using biological response modifiers to improve, alleviate, treat or prevent angiotensin II receptor-related diseases.

In the present invention, the solid dispersion can be used for the preparation of a medicament for preventing or treating an angiotensin II receptor-related disease.

The present invention provides a method for treating stroke, cerebral apoplexy, cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, Kuzard's disease, diabetes, obesity, hyperlipidemia, coronary artery disease, A method of angina pectoris, myocardial infarction, hypertension, heart failure or inflammation, wherein the aforementioned method comprises a step in which the solid dispersion is administered at a therapeutically effective dose.

The present invention provides a method for inhibiting the activation of angiotensin II receptor, comprising a step of administering a solid dispersion at a therapeutically effective dose.

Beneficial effect

The solid dispersion of the present invention, which includes fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable base, which increases famasartan The solubility of the compound increases its dissolving effect, thereby increasing its bioavailability.

In the following, in order to better understand the present invention, it will be described in detail through examples. However, the following examples are only used to illustrate the present invention, but not to limit the scope of the present invention. The embodiments of the present invention are provided to more completely describe the present invention to those skilled in the art.

Examples 1 : Preparation of non-masartan potassium trihydrate and HPMC Solid dispersion

A mixed solution of 1.0 kg of pure water and 1.0 kg of ethanol was used to prepare a solution containing 0.4 kg of non-masartan potassium trihydrate and 0.2 kg of HPMC. The obtained solution was sprayed on a powder layer containing a mixture (0.4 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

Examples 2 : Preparation of non-masartan tosylate and HPMC Solid dispersion

A mixed solution of 0.4 kg of pure water and 1.0 kg of methanol was used to prepare a solution containing 0.5 kg of non-masartan tosylate and 0.2 kg of HPMC. The obtained solution was sprayed on a powder layer containing a mixture (0.4 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

Examples 3 : Preparation of non-masartan ammonia salt and HPMC Solid dispersion

A mixed solution of 0.5 kg of pure water and 2.1 kg of methanol was used to prepare a solution containing 0.3 kg of non-masartan ammonia salt and 0.2 kg of HPMC. The obtained solution was sprayed on a powder layer containing a mixture (0.4 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

Examples 4 : Preparation of non-masartan potassium trihydrate and Eudragit EPO Solid dispersion

A mixed solution of 1.2 kg of pure water and 1.2 kg of ethanol was used to prepare a solution containing 0.4 kg of non-masartan potassium trihydrate and 0.2 kg of HPMC. The obtained solution was sprayed on a powder layer containing a mixture (0.4 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

Examples 5 : Preparation of non-masartan potassium trihydrate and PVA Solid dispersion

A mixed solution of 1.8 kg of pure water and 1.2 kg of ethanol was used to prepare a solution containing 0.4 kg of non-masartan potassium trihydrate and 0.2 kg of PVA. The obtained solution was sprayed on a powder layer containing a mixture (0.4 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

Examples 6 : Preparation of non-masartan potassium trihydrate and HPC Solid dispersion

A solution of 0.4 kg of pure water and 1.5 kg of methanol was used to prepare a solution containing 0.4 kg of non-masartan potassium trihydrate and 0.2 kg of HPC. The obtained solution was sprayed on a powder layer containing a mixture (0.4 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

Examples 7 : Preparation of non-masartan free base and HPC Solid dispersion

A solution containing 0.2 kg of acetone and 0.5 kg of methanol was used to prepare a solution containing 0.3 kg of non-masartan free base and 0.1 kg of HPC. The obtained solution was sprayed on a powder layer containing a mixture (0.3 kg) of mannitol, dicalcium phosphate and sodium methylol starch at a temperature of 50 to 60 ° C by means of a flow layer granulator. The obtained product was dried to obtain a powder. The resulting powder was sieved (0.8 mm) to prepare a solid dispersion.

The solid dispersions prepared in the foregoing Examples 1 to 7 may be used directly, or may be further formulated into dosage forms such as granules, capsules, or lozenges.

Examples 8 : Preparation of non-masartan potassium trihydrate and HPMC Lozenges of solid dispersions

The solid dispersion of Example 1 was mixed with 121 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

Examples 9 : Preparation of tosylate containing non-masartan and HPMC Lozenges of solid dispersions

The solid dispersion of Example 2 was mixed with 104 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

Examples 10 : Preparation of non-masartan ammonia salt and HPMC Lozenges of solid dispersions

The solid dispersion of Example 3 was mixed with 123 grams of mannitol, 14 grams of croscarmellose sodium, and 3 grams of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

Examples 11 : Preparation of non-masartan potassium trihydrate and Eudragit EPO Lozenges of solid dispersions

The solid dispersion of Example 4 was mixed with 120 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

Examples 12 : Preparation of non-masartan potassium trihydrate and PVA Lozenges of solid dispersions

The solid dispersion of Example 5 was mixed with 120 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

Examples 13 : Preparation of non-masartan potassium trihydrate and HPC Lozenges of solid dispersions

The solid dispersion of Example 6 was mixed with 120 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

Examples 14 : Preparation of non-masartan free base and HPC Lozenges of solid dispersions

The solid dispersion of Example 7 was mixed with 124 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The easily pressurized combination product is compressed into a tablet containing 30 mg or 60 mg of non-masartan potassium through a single-punch tablet molding press.

The solid dispersion-containing lozenges prepared in the foregoing Examples 8 to 14 can be further film-coated, so that the lozenges can be protected from light and moisture.

Experimental example 1. Comparison of dissolution rates between solid dispersions and felsartan

The drug dissolution rate experiment of the novel solid dispersion combination finished products in Examples 1 to 7 was performed by the dissolution rate test method described in the Korean Pharmacopoeia (KP). The method was performed at 37 ± 0.5 ° C and a paddle. The paddle method (dissolution device II) was performed at a speed of 75 rpm. The first fluid used for the KP disintegration test (pH 1.2) and 500 ml of sodium acetate buffer solution (pH 4.0) were used as dissolution media. A solid dispersion equivalent to 240 mg of non-masartan potassium was inserted into each container. During the dissolution process, a test sample was taken out through a filter, and the amount of drug dissolved was analyzed by HPLC.

FIG. 1 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersions prepared in Examples 1, 4, 5, and 6 with felsartan potassium trihydrate at a pH value of 1.2.

FIG. 2 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersion prepared in Examples 2, 3, and 7 with various forms of non-masartan salts at a pH value of 1.2, that is, non-massartan tosylate Salt, non-masartan ammonia salt and non-masartan free base were compared.

From the dissolution rate results of femasartan, its salts, or its hydrates shown in FIG. 1 and FIG. 2, it is shown that only about 40% of it is administered at a concentration of 480 mg / ml due to its low solubility. Be dissolved. However, it can be confirmed that the results of this experimental example show that the active material of the solid dispersion of the present invention is rapidly and almost completely dissolved.

Although the solubility of non-masartan potassium trihydrate in the medium at 37 ° C is 0.1 mg / ml, the novel pharmaceutical composition of the present invention is dissolved in an amount close to 100% solubility, which is 0.45 at 37 ° C mg / ml. It was dissolved in 80% in 30 minutes and held for a certain amount (or higher) for 1 hour. Comparing felsartan, its salts or hydrates with the dissolved drug solution of the solid dispersion of the present invention, it can be determined that the solubility of the solid dispersion of the present invention is comparable to that of felsartan, its salts or its hydrate The amount has increased by 1.5 to 24 times.

FIG. 3 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersions prepared in Examples 1, 4, 5, and 6 with felsartan potassium trihydrate at pH 4.0.

FIG. 4 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersions prepared in Examples 2, 3, and 7 with various forms of non-masartan salts at a pH value of 4.0, that is, non-massartan tosylate Salt, non-masartan ammonia salt and non-masartan free base were compared.

Figures 3 and 4 show that the solubility of non-masartan or its salts in the medium is very low (less than 0.01 mg / ml at 37 ° C), and the solid dispersion of the present invention improves this low solubility.

Comparing felsartan or a salt thereof with a dissolved drug solution of the solid dispersion of the present invention, it can be determined that the solid dispersion of the present invention has a significant increase in solubility compared to felsartan or a salt thereof by 10 times to 64 times.

In addition, the results show that the increase in the solubility of the solid dispersion of the present invention tends to be as long as one hour. Therefore, it can be confirmed that the solid dispersion of the present invention forms a supersaturated solution at a fast and high dissolution rate, and has excellent stability sufficient to maintain the solubility of the supersaturated solution.

Based on the above results, it is expected that the solid dispersion of the present invention can achieve excellent absorption rate, bioavailability, and efficacy.

Experimental example 2. Solid dispersion and Kanarb Comparison of dissolution rates between ingots

The drug dissolution rate test of the pharmaceutical composition in Example 8 was performed using the dissolution rate test method described in the Korean Pharmacopoeia (KP). This method was performed at 37 ± 0.5 ° C and a paddle speed of 50 rpm by a paddle method (dissolution Device II). The first fluid used for the KP disintegration test (pH 1.2) and 900 ml of sodium acetate buffer solution (pH 4.0) were used as dissolution media. One lozenge is inserted into the container, which is equivalent to 60 mg of felsartan potassium. During the dissolution process, a test sample was taken out through a filter, and the amount of drug dissolved was analyzed by HPLC. The comparison product was Kanarb lozenge (trade name) containing 60 mg of non-masartan potassium salt.

The dissolution results for each pH are reported in Tables 1 and 2 below.

Table 1

Table 2

FIG. 5 is a comparison diagram comparing a lozenge containing the solid dispersion of Example 8 with a comparative product, a 60 mg lozenge of Kanarb, at a pH of 1.2.

FIG. 6 is a comparison diagram comparing a lozenge containing the solid dispersion of Example 8 with a comparative product, that is, a Kanarb 60 mg lozenge, at a pH value of 4.0.

The results from Table 1 and FIG. 5 show that Kanarb has a dissolution rate of about 55% at a pH value of 1.2, but at a pH value of 1.2, the dissolution rate of a tablet containing the solid dispersion of the present invention is 85% or higher.

In addition, the results of Table 2 and FIG. 6 show that the dissolution rate of the tablets containing the solid dispersion of the present invention is 72%, and the dissolution rate of Kanarb is about 10% at a pH value of 4.0. This result indicates that the dissolution rate of the aforementioned lozenge is at least 7 times higher than that of the existing Kanarb. Therefore, it can be confirmed that the dissolution rate of the solid dispersion of the present invention is greatly improved.

Experimental example 3. Solid dispersion and Kanarb Comparison of oral bioavailability between tablets

Eight beagle dogs weighing about 10 kg were selected, and any food other than water was forbidden for 15 hours before the test materials were given, after which the dogs were given oral Kanarb lozenges (as a control group) and in Example 8 Preparation of lozenges.

The comparison product and the test product were administered at a dose equivalent to 30 mg of femasartan potassium salt per individual. Blood was collected 0, 10, 20, and 30 minutes before drug administration and 1, 2, 3, 4, 6, 8, and 12 hours after drug administration, respectively. Thereafter, the blood sample is centrifuged (about 5 minutes) to obtain plasma, and then transferred to a vial that has been appropriately labeled, then frozen and stored (-20 ° C) until drug analysis. Concerning the drug concentration, plasma samples were analyzed by LC / MS / MS, the pharmacokinetic parameters were calculated, and the results are described in Table 3 below.

table 3

As shown in Table 3 above, the maximum blood drug concentration (C _max ) of the tablet of Example 8 increased by 2.4 times and the area under the curve (AUC) increased by 1.7 compared to the comparative product, that is, Kanarb tablets (registered trade name) Times. Therefore, it was confirmed that the solid dispersion of the present invention can improve drug absorption and bioavailability.

no

FIG. 1 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersions prepared in Examples 1, 4, 5, and 6 with felsartan potassium trihydrate at a pH value of 1.2.

FIG. 2 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersion prepared in Examples 2, 3, and 7 with various forms of non-masartan salts at a pH value of 1.2, that is, non-massartan tosylate Salt, non-masartan ammonia salt and non-masartan free base were compared.

FIG. 3 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersions prepared in Examples 1, 4, 5, and 6 with felsartan potassium trihydrate at pH 4.0.

FIG. 4 is a comparison diagram of the dissolution rate of a drug, which compares the solid dispersions prepared in Examples 2, 3, and 7 with various forms of non-masartan salts at a pH value of 4.0, that is, non-massartan tosylate Salt, non-masartan ammonia salt and non-masartan free base were compared.

FIG. 5 is a comparison diagram comparing a lozenge containing the solid dispersion of Example 8 with a comparative product, a 60 mg lozenge of Kanarb, at a pH of 1.2.

FIG. 6 is a comparison diagram comparing a lozenge containing the solid dispersion of Example 8 with a comparative product, that is, a Kanarb 60 mg lozenge, at a pH value of 4.0.

Claims (15)

A solid dispersion comprising a fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; and A pharmaceutically acceptable matrix. The solid dispersion according to item 1 of the scope of the patent application, wherein the pharmaceutically acceptable matrix is a polymer-type excipient or a non-polymer-type excipient. The solid dispersion according to item 1 of the scope of the patent application, wherein the pharmaceutically acceptable matrix is a polymer-based excipient. The solid dispersion according to item 1 of the scope of patent application, wherein the pharmaceutically acceptable matrix is selected from the group consisting of hydroxyalkylmethyl cellulose, hydroxyalkyl cellulose, carboxymethyl cellulose, sodium carboxymethyl Cellulose, ethyl cellulose, cellulose succinate, cellulose phthalate, polymethacrylate, polyhydroxyalkyl acrylate, polyhydroxyalkyl methacrylate, polyacrylate, polyvinyl alcohol, poly Vinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate copolymer, cross-linked polyvinyl pyrrolidone (crospovidone), polyalkylene glycol, polyethylene oxide, poloxamer, polyvinyl acetate, vinyl alcohol / One or two or more of the group consisting of vinyl acetate copolymer, xanthan gum, keto acid, alginic acid and its salts, polylactic acid and dextrin. The solid dispersion according to item 1 of the scope of the patent application, wherein the pharmaceutically acceptable matrix is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), and hydroxypropyl cellulose ( One or two or more of the group consisting of HPC) and polymethacrylate. The solid dispersion according to item 4 of the scope of the patent application, wherein the polymethacrylate is Eudragit EPO. The solid dispersion according to item 1 of the scope of the patent application, wherein the weight ratio of the non-masartan, its pharmaceutically acceptable salts, or its hydrate or solvate to the matrix is 1: 0.1 to 1: 10. The solid dispersion according to item 1 of the scope of patent application, wherein the pharmaceutically acceptable salt of non-masartan is selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonates, and amino salts And amine salts. The solid dispersion according to item 1 of the scope of patent application, wherein the non-masartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is selected from the group consisting of non-masartan, non-masartan Potassium, non-masartan potassium trihydrate, non-masartan tosylate, and non-masartan ammonium. A pharmaceutical composition for preventing or treating an angiotensin II receptor-related disease, comprising the solid dispersion according to any one of claims 1 to 9 of the scope of patent application, and a pharmaceutically acceptable additive . The pharmaceutical composition for preventing or treating an angiotensin II receptor-related disease as described in item 10 of the scope of patent application, wherein the pharmaceutical composition is for oral administration. The pharmaceutical composition for preventing or treating angiotensin II receptor-related diseases as described in item 10 of the scope of patent application, wherein the angiotensin II receptor-related diseases are selected from the group consisting of stroke and cerebral apoplexy , Cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, kuja's disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure and inflammation One or two or more of the groups. The use of a solid dispersion according to any one of claims 1 to 9 of the scope of patent application for the preparation of a medicament for preventing or treating angiotensin II receptor-related diseases. A treatment for stroke, cerebral apoplexy, cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, Cuzard's disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardium Method of infarction, hypertension, heart failure or inflammation, wherein the method includes a step of performing the solid dispersion as described in any one of claims 1 to 9 of the scope of patent application at a therapeutically effective dose Apply. A method for inhibiting angiotensin II receptor activation, comprising a step of administering the solid dispersion according to any one of claims 1 to 9 of the scope of the patent application at a therapeutically effective dose.